KR20210102900A - 7-phenoxy-N-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[ as a gamma-secretase modulator for the treatment of Alzheimer's disease 1,2-b][1,2,4]triazol-2-amine derivatives and related compounds - Google Patents

Abstract

(I)
본 발명의 화합물은 뇌에서의 β-아밀로이드 침착과 관련된 질환, 가령, 알츠하이머 병, 뇌 아밀로이드 혈관병증, 달팽이관 시냅스병증, 청력 소실, 아밀로이드증을 동반한 유전성 뇌출혈-네덜란드 형 (HCHWA-D), 다경색성 치매, 권투선수 치매 또는 다운 증후군의 치료를 위한 감마-세크레타제 조절제로서 존재한다. 본 명세서는 예시적인 화합물들의 제조 및 이의 약리학적 데이터를 개시한다 (예컨대 실시예 1 내지 64; 표). 화합물의 한 예는 (R)-7-(3,5-다이플루오로페녹시)-N-((IR,5S,8s)-3-(6-메톡시피리다진-4-일)-3-아자바이사이클로[3.2.1]옥탄-8-일)-6,7-다이하이드로-5H-피롤로[1,2-b][1,2,4]트라이아졸-2-아민 (실시예 1)이다.The present invention relates to 7-phenoxy-N-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b of formula (I) ][1,2,4]triazol-2-amine derivatives and related compounds wherein R ¹ , Ar, n and m are as described herein, compositions comprising such compounds, processes for preparing such compounds and Provided is a compound for use in a method of medical treatment:

(I)
The compounds of the present invention are suitable for diseases associated with β-amyloid deposition in the brain, such as Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D), multi-infarction It exists as a gamma-secretase modulator for the treatment of sexual dementia, boxer's dementia or Down's syndrome. This specification discloses the preparation of exemplary compounds and their pharmacological data (eg Examples 1-64; Table). One example of a compound is (R)-7-(3,5-difluorophenoxy)-N-((IR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3 -azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine (Example 1) is.

Description

7-phenoxy-N-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[ as a gamma-secretase modulator for the treatment of Alzheimer's disease 1,2-b][1,2,4]triazol-2-amine derivatives and related compounds

The present invention relates to bicyclic heteroaryl compounds useful as gamma (γ)-secretase modulators, their preparation, pharmaceutical compositions comprising said compounds, and diseases associated with β-amyloid deposition in the brain, such as Alzheimer's disease, brain amyloid Its as medicament for the therapeutic and/or prophylactic treatment of angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia or Down's syndrome It's about use.

Alzheimer's disease (AD) is the most common cause of dementia in old age. Pathologically, AD is characterized by amyloid deposition in extracellular plaques and intracellular neurofibrillary tangles in the brain. Amyloid plaques are mainly composed of amyloid peptides (Aβ peptides) derived from β-amyloid precursor protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified, the most abundant of which are proteins with a length of 695, 751 and 770 amino acids. They all occur through differential splicing from a single gene. These Aβ peptides are derived from the same domain of APP.

Aβ peptides are produced from APP through the sequential action of two proteolytic enzymes called β- and γ-secretases. β-secretase is first cleaved in the extracellular domain of APP just outside the transmembrane domain (TM) to generate a C-terminal fragment of APP (CTFb) comprising the TM- and cytoplasmic domains. CTFb is a substrate for γ-secretase, which is cleaved at several contiguous positions within the TM to generate Ab peptides and cytoplasmic fragments. Various proteolytic cleavage mediated by γ-secretase yields Aβ peptides of different chain lengths, such as Aβ38, Aβ40 and Aβ42. The latter are considered more pathogenic amyloid peptides because of their strong tendency to form neurotoxic aggregates. β-secretase is a typical aspartyl protease.

γ-secretase is composed of four essential subunits: presenilin (including PS, PS1 and PS2), nicastrin, prepharyngeal defect 1 (APH-1) and presenilin enhancer 2 (PEN-2). It is a high molecular weight complex. The atomic structure of human γ-secretase at 3.4 Å resolution has been published (X. Bai, C. Yan, G. Yang, P. Lu, D. Ma, L. Sun, R. Zhou, SHW Scheres, Y. Shi, Nature, 525 (2015), 212 - 217). Presenilin has a catalytic site and represents a family of atypical aspartyl proteases that cleave substrates within the TM and are themselves polytopic membrane proteins. γ-secretase, nicastrin and other essential components of the products of the aph1 and pen-2 genes are believed to be responsible for substrate recognition and recruitment. Proven substrates for γ-secretase are proteins of the APP and Notch receptor families, but γ-secretase has a loose substrate specificity and many additional membrane proteins unrelated to APP and Norch are γ-secretase in vitro. It has been reported to be cleaved by

γ-secretase activity is absolutely necessary for the production of Aβ peptides. This was demonstrated by both genetic means, namely, deletion of the presenilin gene and low molecular weight inhibitory compounds. According to the amyloid cascade hypothesis for AD, the production and deposition of Aβ is the ultimate cause of the disease. Therefore, it is believed that selective and potent inhibition of γ-secretase may be useful in the prevention and treatment of AD.

An alternative treatment modality is modulation of γ-secretase activity that selectively reduces Aβ42 production. This would result in an increase in shorter Aβ isoforms, such as Aβ38, Aβ37 or others, with no or reduced ability to aggregate and form plaques and with no or less neurotoxicity. Compounds that modulate γ-secretase activity include certain non-steroidal anti-inflammatory drugs (NSAIDs) and related analogs (Weggen et al., Nature , 414 (2001) 212-216).

Numerous documents, such as the following publications, describe current knowledge of γ-secretase regulation: Morihara et al ., J. Neurochem ., 83 (2002), 1009-12; Jantzen et al. , J. Neuroscience , 22 (2002), 226-54; Takahashi et al ., J. Biol. Chem. , 278 (2003), 18644-70; Beher et al ., J. Biol. Chem., 279 (2004), 43419-26; Lleo et al., Nature Med., 10 (2004), 1065-6; Kukar et al., Nature Med., 11 (2005), 545-50; Perretto et al ., J. Med. Chem., 48 (2005), 5705-20; Clarke et al ., J. Biol. Chem., 281 (2006) 31279-89; Stock et al ., Bioorg. Med. Chem. Lett. , 16 (2006) 2219-2223; Narlawar et al ., J. Med. Chem., 49 (2006) 7588-91; Ebke et al ., J. Biol. Chem. , 286 (2011) 37181-86; Oehlich, Gijsen et al ., J. Med. Chem. , 54 (2011), 669 - 698; Li et al. , Biochemistry , 52 (2013), 3197 - 3216; Hall et al. , Progress in Med. Chem. , 53 (2014) 101-145; Bursavich et al ., J. Med. Chem. , 59 (2016); WO 2018/111926.

Therefore, modulation of γ-secretase activity may be associated with diseases associated with β-amyloid deposition in the brain, such as Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA). -D), is a promising therapeutic strategy to treat or prevent multi-infarct dementia, boxer's dementia and Down's syndrome.

There is a need for new compounds, agents, therapies and therapeutics to treat diseases and disorders associated with β-amyloid deposition in the brain. It is therefore an object of the present invention to provide compounds useful for the treatment or prophylaxis of such diseases and disorders having improved therapeutic properties.

A first object of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof:

(I)

(I)

In the above formula,

R ¹ is halogen, lower alkyl, lower alkyl substituted with halogen, lower alkoxy or lower alkoxy substituted with halogen,

^{R 1} may be different when n is 2 or 3;

m is 1, 2 or 3;

n is 1, 2 or 3;

및

에서 선택되는 6원 헤테로아릴 기이고;Ar is

and

a 6-membered heteroaryl group selected from;

R ² is hydrogen, halogen, lower alkyl, lower alkyl substituted with halogen, or lower alkoxy;

R ³ is hydrogen or halogen.

Another object of the present invention is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, comprising the steps of reacting compound 7 below with amine 8 to form a compound of formula (I) and, if necessary, converting these compounds into pharmaceutically acceptable salts thereof:

7

7

8

8

wherein Ar, R ¹ , n and m are as defined above.

Another object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, prepared according to the process described above.

Another object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Another object of the present invention is the treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome A compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in therapeutic and/or prophylactic treatment.

Another object of the present invention is the treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for therapeutic and/or prophylactic treatment.

Another object of the present invention is the treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the manufacture of a medicament for therapeutic and/or prophylactic treatment.

Another object of the present invention is the treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome A method of therapeutic and/or prophylactic treatment comprising administering an effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

The following definitions of generic terms used in this description apply regardless of whether the terms are used alone or in combination with other groups.

The term "lower alkyl", alone or in combination with other groups, refers to a saturated straight or branched chain alkyl group having single or multiple branches, wherein the alkyl group generally contains 1 to 7 carbon atoms ("C _1-7 - alkyl"), for example methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t -butyl (tert-butyl), isopentyl, 2-ethyl-propyl, 1,2-dimethyl-propyl, and the like. Certain lower alkyl groups have from 1 to 4 carbon atoms (“C _1-4 -alkyl”).

The term "lower alkyl substituted with halogen" refers to an alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen, preferably fluorine, eg CF ₃ , CHF ₂ , CH ₂ F, CHFCF ₃ , CH ₂ CHF ₂ , CH ₂ CH ₂ F , CH ₂ C(CH ₃ ) ₂ CF ₃ , CH ₂ CF ₂ CF ₃ , CH(CF ₃ ) ₂ , CH ₂ CF ₃ , (CH ₂ ) ₂ CF ₃ , ( CH ₂ ) ₃ CF ₃ , CH(CH ₃ )CF ₃ , CF ₂ CF ₃ , and the like. A preferred group is CF ₃ .

The term "alkoxy", alone or in combination, refers to a group of the formula alkyl-O- wherein the term "alkyl" has the meaning given above and is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , isobutoxy, sec-butoxy and tert-butoxy are examples. Particular "alkoxy" is methoxy and tert-butyloxy.

The term "lower alkoxy substituted by halogen" denotes a lower alkoxy group as defined above wherein at least one hydrogen atom has been replaced by a halogen, preferably fluorine.

The term "halogen" or "halo", alone or in combination, denotes fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term "halo" in combination with another group refers to the substitution of said group with at least one halogen, in particular with 1 to 5 halogens, in particular 1 to 4 halogens, ie with 1, 2, 3 or 4 halogens. represents substitution.

The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. These salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, Formed using tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine.

Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

The term "protecting group" (PG), in the meaning normally associated therewith in synthetic chemistry, refers to a group that selectively blocks a reactive site in a polyfunctional compound, allowing a chemical reaction to be carried out selectively at another unprotected reactive site. At appropriate points the protecting group may be removed. Exemplary protecting groups are amino protecting groups, carboxy protecting groups or hydroxy protecting groups. Particularly protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). More particularly protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). More particularly the protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their application in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry", 5th Ed., 2014, John Wiley & Sons, NY by TW Greene and PGM Wutts.

The terms "asymmetric carbon atom" and "asymmetric center" mean a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog convention, an asymmetric carbon atom can be of either an "R" or an "S" structure.

The following abbreviations are used herein:

Boc = tert-butoxycarbonyl, CAS RN = Chemical Abstract Accession Number, DIAD = diisopropyl azodicarboxylate, DMF = dimethylformamide, EtOAc = ethyl acetate, EtOH = ethanol, FCS = fetal calf serum, GCMS = gas chromatography mass spectrometry, h = time(s), Hal = halogen, Hept = heptane, HPLC = high performance liquid chromatography, IMDM = Iscove's modified Dulbecco's medium, LCMS = liquid chromatography mass spectrometry, MeCN = acetonitrile , MeOH = methanol, Me ₂ SO = dimethylsulfoxide (DMSO), MOM = methoxymethyl, min = min(s), ml = milliliter, μl = microliter, MS = mass spectrum, NaOMe = sodium methoxide, NaOtBu = sodium tert-butyloxide, nBuLi = n-butyllithium, NEt ₃ = triethylamine (TEA), NMP = N-methyl-2-pyrrolidone, OAc = acetoxy, Pd ₂ (dba) ₃ = tris (dibenzylideneacetone)dipalladium(0), p-TsOH = p-toluenesulfonic acid, R = any group, RT = room temperature, SFC = supercritical fluid chromatography, tBuXPhos = 2-di-tert-butyl Phosphino-2',4',6'-triisopropylbiphenyl, TBME = tert-butylmethylether, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, THP = tetrahydro piran.

compounds of the present invention

In a first aspect, the present invention provides a compound of formula (I):

(I)

(I)

In the above formula,

R ¹ is halogen, lower alkyl, lower alkyl substituted with halogen, lower alkoxy or lower alkoxy substituted with halogen,

^{R 1} may be different when n is 2 or 3;

m is 1, 2 or 3;

n is 1, 2 or 3;

및

에서 선택되는 6원 헤테로아릴 기이고;Ar is

and

a 6-membered heteroaryl group selected from;

R ² is hydrogen, halogen, lower alkyl, lower alkyl substituted with halogen, or lower alkoxy;

R ³ is hydrogen or halogen.

In one embodiment, provided herein is a compound of formula (I), wherein the compound of formula (I) is a compound of formula (Ia): or a pharmaceutically acceptable salt thereof:

(Ia)

(Ia)

wherein R ¹ , m, n and Ar are as defined above.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein the compound of formula (I) is a compound of formula (lb): or a pharmaceutically acceptable salt thereof:

(Ib)

(Ib)

wherein R ¹ , m, n and Ar are as defined above.

In one embodiment, R ¹ is halogen.

In one embodiment, R ¹ is fluorine or chlorine.

In one embodiment, m is 1 or 2.

및

에서 선택된 6원 헤테로아릴 기이고;In one embodiment, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ar is

and

a 6 membered heteroaryl group selected from;

R ² is lower alkyl or lower alkoxy;

R ³ is hydrogen.

및

에서 선택된 6원 헤테로아릴 기이고;In another preferred embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Ar is

and

a 6 membered heteroaryl group selected from;

R ² is methyl or methoxy;

R ³ is hydrogen.

In a further preferred embodiment there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

R ¹ is halogen;

m is 1 or 2;

n is 1, 2 or 3;

및

에서 선택되는 6원 헤테로아릴 기이고;Ar is

and

a 6-membered heteroaryl group selected from;

R ² is lower alkyl or lower alkoxy;

R ³ is hydrogen.

In a further preferred embodiment there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

R ¹ is fluorine or chlorine,

m is 1 or 2;

n is 1, 2 or 3;

및

에서 선택되는 6원 헤테로아릴 기이고;Ar is

and

a 6-membered heteroaryl group selected from;

R ² is methyl or methoxy;

R ³ is hydrogen.

A compound of formula (I), or a pharmaceutically acceptable salt thereof, may contain one or more asymmetric centers and may contain optically pure enantiomers, mixtures of enantiomers such as racemates, mixtures of diastereomers, It may exist in the form of a diastereomeric racemate or a mixture of diastereomeric racemates.

In a further embodiment there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from:

(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2 ,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2 ,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;

(S)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2 ,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2 ,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;

(R)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine; and

(S)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine.

In a further embodiment there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from:

(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;

(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine; and

(S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

Manufacture process

A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, described herein is also an object of the present invention.

The preparation of the compounds of formula (I) described herein may be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is represented by the following general reaction scheme. The techniques necessary to carry out the reaction and purification of the resulting product are known to those skilled in the art. Substituents and indices used in the following description of the preparation method have the meanings provided hereinabove unless otherwise indicated.

When one of the starting materials, intermediates or compounds of formula (I) of the present invention contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, methods well known in the art are applied. Appropriate protecting groups (eg, described in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, 3rd Ed., 1999, Wiley, New York) may be introduced prior to the critical step of These protecting groups can be removed at later stages of the synthesis using standard methods described in the literature. Examples of protecting groups include tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxy benzyloxycarbonyl (Moz).

If the starting materials or intermediates contain stereocenters, the compounds of formula (I) can be obtained as diastereomers or mixtures of enantiomers, which are prepared by methods well known in the art, for example chiral HPLC, chiral SFC or by chiral crystallization. Racemic compounds can be separated into enantiomers via diastereomeric salts, for example, by crystallization with optically pure acids or by enantiomer separation by specific chromatographic methods using chiral adsorbents or chiral eluents. have. It is likewise possible to isolate starting materials and intermediates comprising stereocenters to provide diastereomerically/enantiomerically enriched starting materials and intermediates. The use of these diastereomerically/enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) generally results in diastereomerically/enantiomerically enriched compounds of formula (I), respectively will be

One of ordinary skill in the art will appreciate that the order of reactions may vary depending on the reactivity and nature of the intermediates.

More specifically, the compounds of formula (I) can be prepared by the methods given below, by the methods given in the Examples, or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Also, for reaction conditions described in the literature affecting the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999 ). It has been found convenient to carry out the reaction in the presence or absence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it does not have a detrimental effect on the reaction or the reagent involved and that it can dissolve the reagent at least to some extent. The reactions described can occur over a wide range of temperatures and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the reactions described in the temperature range from -78 °C to reflux. The time required for the reaction can vary greatly depending on many factors, in particular the reaction temperature and the properties of the reagents. However, a period of 0.5 hours to several days is usually sufficient to yield the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the sequence of the reaction steps can be freely changed according to the starting materials and their respective reactivity.

When starting materials or intermediates are not commercially available or their synthesis has not been described in the literature, they can be prepared analogously to existing procedures for close analogs or as described in the experimental section.

In one embodiment, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, comprises reacting compound 7 with an amine 8 to form a compound of formula (I), case, it is prepared by a method comprising the step of converting these compounds into pharmaceutically acceptable salts thereof:

7

7

8

8

wherein Ar, R ¹ , n and m are as described herein.

In one embodiment, the process according to the invention comprises in the presence of a catalyst, for example palladium, optionally a ligand, for example 2-di-tert-butylphosphino-2',4',6'-tri in the presence of isopropylbiphenyl.

In a further embodiment, the method according to the invention may further comprise the step of carrying out chiral separation to obtain compounds of formulas (Ia) and (Ib).

In one embodiment ^{, the compounds of formula (I) and intermediates thereof, wherein R 1} , n, m and Ar are as described herein, are analogous to literature procedures and/or procedures, for example, shown in Schemes 1 and 2, respectively. can be manufactured.

[Scheme 1]

The preparation of compounds of formula (I) can begin by protecting 3,5-dibromo-1H-1,2,4-triazole 2 with a MOM group to give 3. Regioselective halo lithiation with nBuLi followed by addition of aldehydes (m=1,2 or 3) as carbon chain electrophiles of different lengths gave alcohol 4 . Mitsunobu coupling was then performed using different phenols to give the aryl ether derivative 5 . Derivative 6 was obtained after simultaneous deprotection of THP protected primary alcohol and MOM protected triazole under acidic conditions. Then, intramolecular cyclization was performed using cyanomethylenetrimethylphosphorane to give 7 . Finally, Buchwald-type coupling with an amine of formula 8 in the presence of palladium and a ligand gave compounds of formula (I). Preparative chiral HPLC allowed the separation of enantiomers.

[Scheme 2]

Compound 8 shown in Scheme 1 is tert-butyl N-[(1S,5R,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate 9 (CAS RN 847862-26-4) Starting from, it can be prepared according to Scheme 2. Coupling of 9 with a heterocyclic halide of the general formula Ar-X is performed under thermal conditions in a solvent such as ethanol or NMP in the presence of a base such as _{Et 3 N or under catalytic conditions (eg, palladium (0) or copper (II)} ) using a substitution reaction under a catalyst) to give compound 10. After deprotection with an acid such as trifluoroacetic acid, compound 8 is obtained.

Heterocyclic halides are either commercially available or well known in the literature and can be prepared by methods known in the art.

In one aspect, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, prepared according to any one of the processes described herein.

Pharmaceutical Compositions and Administration

Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The compound of formula (I) and its pharmaceutically acceptable salts can be used as a medicament in the form of a pharmaceutical preparation. Pharmaceutical preparations may be administered internally, for example, orally (eg in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasal (eg in the form of a nasal spray) or rectal (eg, in the form of suppositories). However, such administration may also be parenterally, such as intramuscularly or intravenously (eg in the form of an injection solution). Such administration may also be topically, for example, transdermally or in the form of eye drops or drops.

The compounds of formula (I) and their pharmaceutically acceptable salts are prepared as pharmaceutically inert inorganic or organic carriers for the preparation of pharmaceutical preparations, such as tablets, coated tablets, dragees, hard gelatine capsules, injectable solutions or topical preparations. can be processed. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, and the like, can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatine capsules.

Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like. However, depending on the nature of the active substance, no carrier is usually required for soft gelatin capsules.

Suitable carriers for the preparation of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oils and the like.

Suitable carriers for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Suitable carriers for topical ocular formulations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

Moreover, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for changing the osmotic pressure, buffering agents, masking agents or antioxidants. They may also contain other therapeutically useful substances.

A medicament containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is also a subject of the present invention, and also a process for its preparation, wherein the process comprises one or more compounds of formula (I) and/or a pharmaceutically acceptable salt thereof, and, if desired, one or more other therapeutically useful substances, together with one or more pharmaceutically acceptable excipients, into a herbal dosage form.

The dosage may vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In general, for oral administration, a daily dose of about 0.1 mg to 20 mg/kg body weight, preferably 0.5 mg to 4 mg/kg body weight (e.g., about 300 mg per person), will be appropriate. The dose is preferably divided into 1-3 individual doses, which individual doses may, for example, consist of equal quantities. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug and the required dose may be 0.1 to 25 mg, which may be in a single dose per day or weekly, or in multiple doses per day (2 to 25 mg). 4), or as multiple doses per week. It will be evident, however, that any upper or lower limit given herein may be exceeded when shown as indicated.

The pharmaceutical composition according to the present invention can be prepared as follows.

Preparation of a pharmaceutical composition comprising a compound of the present invention

Tablet formulation (wet granulation)

Manufacturing procedure:

One. Ingredients 1, 2, 3 and 4 are mixed and granulated with purified water.

2. Dry the granules at 50 °C.

3. Pass the granules through suitable grinding equipment.

4. Add component 5 and mix for 3 minutes; Pressurize to the appropriate pressure.

capsule formulation

Manufacturing procedure:

1. Mix components 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Fill in suitable capsules.

indication

Also an object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

As described above, compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as gamma-secretase modulators.

In one aspect, the invention provides a treatment for Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome. Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in therapeutic and/or prophylactic treatment.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and/or prophylactic treatment of Alzheimer's disease.

In another aspect, the invention relates to Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome Provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the therapeutic and/or prophylactic treatment of

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and/or prophylactic treatment of Alzheimer's disease.

In another aspect, the invention relates to Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome Provided is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease.

In another aspect, the invention relates to Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, boxer's dementia, or Down's syndrome Provided is a method for the therapeutic and/or prophylactic treatment of

In one embodiment, the present invention provides a method for the therapeutic and/or prophylactic treatment of Alzheimer's disease comprising administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

Example

The present invention will be more fully understood by reference to the following examples. However, the claims should not be construed as being limited to the scope of these examples.

1) Preparation example

1.1) General

Analytical Method: HPLC (Method LCMS_Fast Gradient)

- Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1x30 mm, 1.8 μm

- Solvent A: water 0.01% formic acid; Solvent B: acetonitrile (MeCN)

- Concentration gradient:

1.2) Preparation of intermediates

1.2.1) intermediates of type 7 with m=1

intermediate 7-1 : 2-bromo-7- (3,5-difluorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole

Step 1: 3,5-Dibromo-1H-1,2,4-triazole (10 g, 44.1 mmol, Eq: 1) was combined with DMF (175 ml) to give a pale yellow solution. Under stirring and argon, sodium hydride (60% in oil) (2.12 g, 52.9 mmol, Eq: 1.2) is added in portions over a period of 45 min at up to 25°C (up to 250 mg), then 1 h at RT. stirred. Chloro(methoxy)methane (3.55 g, 3.35 ml, 44.1 mmol, Eq: 1) was added dropwise at up to 25 °C over a period of 20 min and then stirred under argon for 2 h at RT. The reaction mixture was poured into ice water (400 ml) and extracted 3 times with TBME (600 ml). The organic layer was washed with water (300 ml) followed by brine (300 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (Hept: EtOAc 95:5 to 50:50) to give 3,5-dibromo-1-(methoxymethyl)-1H-1,2,4-triazole as a white solid (10.2). g 85%). MS (ES+) m/z: 272.1 [(M+H) ⁺ ].

Step 2: 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (3 g, 11.1 mmol, Eq: 1) was combined with THF (27 ml) to give a colorless solution was then cooled to -75 °C in a dry ice/acetone bath. N-Butyllithium 1.6 M in hexanes (7.34 ml, 11.7 mmol, Eq: 1.06) was added dropwise over a period of 20 min. The yellow solution was stirred at -75 °C for 45 min. Now a solution of 3-((tetrahydro-2H-pyran-2-yl)oxy)propanal (2.1 g, 13.3 mmol, Eq: 1.2) in THF (27 ml) was added dropwise over a period of 30 min followed by -75 Stir at °C for 45 min. The dry-ice/acetone bath was removed and the reaction was warmed to ca. 15°C over 1 h _{, then quenched with 60 ml of saturated NH 4} Cl-solution, followed by 45 ml water and 90 ml EtOAc. The mixture was stirred for 5 minutes. The layers were separated. The aqueous layer was back extracted with EtOAc (2x 90 ml). The organic layers were washed with brine (60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 80:20 to 0:100) to 1-(3-bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl )-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol was obtained as a colorless oil (3.25 g 83.8%). MS (ES+) m/z: 352.0 [(M+H) ⁺ ].

Step 3: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl) Oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1) was combined with extra dry THF (25 ml) to give a colorless solution, stirred and under argon, 3,5-difluorophenol ( 223 mg, 1.71 mmol, Eq: 1.2) and triphenylphosphine (468 mg, 1.78 mmol, Eq: 1.25) were added. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over a period of 2-3 min at up to +3-5 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3,5-difluorophenoxy)-3-( Obtained (tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (542 mg, 82%). MS (ES+) (−THP) m/z: 378.1/380.1 [(M+H) ⁺ ].

Step 4: 3-Bromo-5-(1-(3,5-difluorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxy Methyl)-1H-1,2,4-triazole (535 mg, 1.16 mmol, Eq: 1) was combined with methanol (9 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.56 g, 3.8 ml, 46.3 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (80 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3, Obtained 5-difluorophenoxy)propan-1-ol as a white solid (350 mg, 90%). MS (ES+) m/z: 334.0 [(M+H) ⁺ ].

Step 5: 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3,5-difluorophenoxy)propan-1-ol (350 mg, 1.05 mmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.62 ml, 1.31 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo [1,2-b][1,2,4]triazole was obtained as a colorless oil (255 mg, 77%). MS (ES+) m/z: 315.9 [(M+H) ⁺ ].

intermediate 7-2 : 2-bromo-7- (3-chloro-5-fluorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl) oxy)propan-1-ol (500 mg, 1.43 mmol, eq: 1, described above), 3-chloro-5-fluorophenol (209 mg, 1.43 mmol, eq: 1) and triphenylphosphine (468 mg , 1.78 mmol, Eq: 1.25) was combined with excess dry THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3-chloro-5-fluorophenoxy)-3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole was obtained as a colorless oil (605 mg, 88%). GCMS (FI+) m/z: 478.9 [(M+H) ⁺ ]

Step 2: 3-Bromo-5-(1-(3-chloro-5-fluorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methyl Toxymethyl)-1H-1,2,4-triazole (600 mg, 1.25 mmol, Eq: 1) was combined with methanol (9.5 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.94 g, 4.12 ml, 50.1 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. Cooled to RT, poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (80 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro 5-Fluorophenoxy)propan-1-ol was obtained as a colorless foam (405 mg, 92%). MS (ES+) m/z: 351.9 [(M+H) ⁺ ].

Step 3: 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro-5-fluorophenoxy)propan-1-ol (405 mg, 1.16 mmol, Eq: 1) was combined with excess dry THF (12.5 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.89 ml, 1.44 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-7-(3-chloro-5-fluorophenoxy)-6,7-dihydro-5H-p Rolo[1,2-b][1,2,4]triazole was obtained as a colorless oil (284 mg, 73%). MS (ES+) m/z: 333.9 [(M+H) ⁺ ].

intermediate 7-3 : 2-Bromo-7- (2,3,4-trifluorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl) Oxy)propan-1-ol (504 mg, 1.44 mmol, Eq: 1, described above), 2,3,4-trifluorophenol (256 mg, 1.73 mmol, Eq: 1.2) and triphenylphosphine (472) mg, 1.8 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (364 mg, 350 μl, 1.8 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-1-(methoxymethyl)-5-(3-((tetrahydro-2H- Obtained pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)propyl)-1H-1,2,4-triazole as a pale yellow oil (632 mg, 91%). did. GCMS (FI+) m/z: 479.0 [(M+H) ⁺ ].

Step 2: 3-Bromo-1-(methoxymethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy) Cy)propyl)-1H-1,2,4-triazole (154 mg, 321 μmol, Eq: 1) was combined with methanol (2.5 ml) to give a colorless solution. 37% HCl in water (1.26 g, 1.05 ml, 12.8 mmol, Eq: 40) was added under stirring and argon. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (10 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (30 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(2,3) Obtained ,4-trifluorophenoxy)propan-1-ol as a colorless viscous oil (106 mg, 93%). MS (ES+) m/z: 353.9 [(M+H) ⁺ ].

Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(2,3,4-trifluorophenoxy)propan-1-ol (102 mg , 290 μmol, Eq: 1) was combined with excess dry THF (3 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (724 μl, 362 μmol, Eq: 1.25) in THF (0.5 M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (20 ml) and saturated sodium bicarbonate solution (3 ml). The aqueous layer was back extracted with EtOAc (2x 20 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H- Pyrrolo[1,2-b][1,2,4]triazole was obtained as a colorless oil (70 mg, 72%). MS (ES+) m/z: 333.9 [(M+H) ⁺ ].

intermediate 7-4 : 2-bromo-7- (4-chlorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl) Oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1, described above), 4-chlorophenol (220 mg, 1.71 mmol, Eq: 1.2) and triphenylphosphine (468 mg, 1.78 mmol, Eq.) : 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-1-(methoxymethyl)-5-(3-((tetrahydro-2H- Pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)propyl)-1H-1,2,4-triazole was obtained as a colorless oil (520 mg, 79%). . MS (ES+) m/z: 462.1 [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(4-chlorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H -1,2,4-triazole (517 mg, 1.12 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.42 g, 3.69 ml, 44.9 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(4-chloro Phenoxy)propan-1-ol was obtained as a white foam (335 mg, 89%). MS (ES+) m/z: 331.9 [(M+H) ⁺ ].

Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(4-chlorophenoxy)propan-1-ol (323 mg, 971 μmol, Eq: 1) was combined with excess dry THF (10 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.43 ml, 1.21 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. Cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100), and 2-bromo-7-(4-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]triazole Obtained as a white solid (240 mg, 78%). MS (ES+) m/z: 315.9 [(M+H) ⁺ ].

intermediate 7-5 : 2-Bromo-7- (3-chlorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl) Oxy)propan-1-ol (500 mg, 1.43 mmol, Eq: 1, described above), 3-chlorophenol (220 mg, 1.71 mmol, Eq: 1.2) and triphenylphosphine (468 mg, 1.78 mmol, Eq.) : 1.25) (468 mg, 1.78 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3-chlorophenoxy)-3-((tetrahydro- Obtained 2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (545 mg, 82%). MS (ES+) m/z: 462.1 [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(3-chlorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H -1,2,4-triazole (540 mg, 1.17 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and under argon, 37% HCl in water (4.62 g, 3.85 ml, 46.9 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3-chloro Phenoxy)propan-1-ol was obtained as a colorless viscous oil (360 mg, 92%). MS (ES+) m/z: 331.9 [(M+H) ⁺ ].

Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(3-chlorophenoxy)propan-1-ol (355 mg, 1.07 mmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.67 ml, 1.33 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-7-(3-chlorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2 -b][1,2,4]triazole was obtained as a colorless oil (249 mg, 74%). MS (ES+) m/z: 315.9 [(M+H) ⁺ ].

intermediate 7-6 : 2-bromo-7- (3,5-dichlorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl) oxy)propan-1-ol (500 mg, 1.43 mmol, eq: 1, described above), 3,5-dichlorophenol (279 mg, 1.71 mmol, eq: 1.2) and triphenylphosphine (468 mg, 1.78) mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (361 mg, 347 μl, 1.78 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3,5-dichlorophenoxy)-3-(( Tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl)-1H-1,2,4-triazole was obtained as a colorless oil (625 mg, 82%). GCMS m/z: 494.0 [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(3,5-dichlorophenoxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-(methoxymethyl )-1H-1,2,4-triazole (620 mg, 1.25 mmol, Eq: 1) was combined with MeOH (10 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.93 g, 4.11 ml, 50.1 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction was then cooled to RT and poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 3-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(3,5) -Dichlorophenoxy)propan-1-ol was obtained as a white foam (408 mg, 88%). MS (ES+) m/z: 367.9 [(M+H) ⁺ ].

Step 3: 3-(3-Bromo-1H-1,2,4-triazol-5-yl)-3-(3,5-dichlorophenoxy)propan-1-ol (400 mg, 1.09 mmol , equivalents: 1) was combined with excess dry THF (11.5 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.72 ml, 1.36 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-7-(3,5-dichlorophenoxy)-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazole was obtained as a colorless oil (288 mg, 75%). MS (ES+) m/z: 349.9 [(M+H) ⁺ ].

1.2.2) intermediates of type 7, with m=2

intermediate 7-7 : 2-Bromo-8- (3-chloro-5-fluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (4 g, 14.8 mmol, Eq: 1, described above) is combined with THF (36 ml) to give a colorless solution and cooled to -75 °C in a dry ice/acetone bath. n-Butyllithium (1.6 M in hexanes, 9.78 ml, 15.7 mmol, Eq: 1.06) was added dropwise over a period of 20 min. The yellow solution was stirred at -75 °C for 45 min. Then a solution of 4-((tetrahydro-2H-pyran-2-yl)oxy)butanal (3.05 g, 17.7 mmol, Eq: 1.2) in THF (36 ml) was added dropwise over a period of 30 minutes and then the mixture was stirred Stir at -75 °C for 45 min. The dry ice/acetone bath was removed and the reaction was warmed to ca. 15°C over 1 h _{, then quenched with 80 ml of saturated NH 4} Cl solution, followed by 55 ml water and 120 ml EtOAc. The mixture was stirred for 5 minutes. The layers were separated. The aqueous layer was back extracted with EtOAc (2x 120 ml). The organic layers were washed with brine (80 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 80:20 to 0:100) to 1-(3-bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl )-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-ol was obtained as a colorless oil (3.75 g 69%). MS (ES+) m/z: 364.0 [(M+H) ⁺ ].

Step 2: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) Oxy)butan-1-ol (500 mg, 1.37 mmol, Eq: 1), 3-chloro-5-fluorophenol (241 mg, 1.65 mmol, Eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol) , Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3-chloro-5-fluorophenoxy)-4- ((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole was obtained as a colorless oil (620 mg, 91%). MS (ES+) m/z: 410.0 (-THP) [(M+H) ⁺ ].

Step 3: 3-Bromo-5-(1-(3-chloro-5-fluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methyl Toxymethyl)-1H-1,2,4-triazole (620 mg, 1.26 mmol, Eq: 1) was combined with MeOH (10 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.96 g, 4.13 ml, 50.3 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3-chloro Obtained -5-fluorophenoxy)butan-1-ol as a colorless, viscous oil (435 mg, 94%). MS (ES+) m/z: 365.9 [(M+H) ⁺ ].

Step 4: 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3-chloro-5-fluorophenoxy)butan-1-ol (430 mg, 1.18 mmol, Eq: 1) was combined with excess dry THF (12 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.95 ml, 1.47 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (70 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back extracted with EtOAc (2x 40 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-8-(3-chloro-5-fluorophenoxy)-5,6,7,8-tetrahydro -[1,2,4]triazolo[1,5-a]pyridine was obtained as a colorless oil (320 mg, 78%). MS (ES+) m/z: 347.9 [(M+H) ⁺ ].

intermediate 7-8 : 2-bromo-8- (3,5-difluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) oxy)butan-1-ol (550 mg, 1.51 mmol, eq: 1, described above), 3,5-difluorophenol (196 mg, 1.51 mmol, eq: 1) and triphenylphosphine (495 mg, 1.89 mmol, Eq: 1.25) was combined with THF (27 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (382 mg, 367 μl, 1.89 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3,5-difluorophenoxy)-4-( Obtained (tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (530 mg, 73%). MS (ES+) m/z: 476.0 [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(3,5-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxy Methyl)-1H-1,2,4-triazole (530 mg, 1.11 mmol, Eq: 1) was combined with MeOH (8.5 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.39 g, 3.65 ml, 44.5 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction was then cooled to RT and poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3,5) Obtained -difluorophenoxy)butan-1-ol as a colorless viscous oil (372 mg, 96%). MS (ES+) m/z: 348.0 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3,5-difluorophenoxy)butan-1-ol (370 mg, 1.06) mmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.66 ml, 1.33 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were washed with brine (80 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro- [1,2,4]triazolo[1,5-a]pyridine was obtained as a colorless oil (254 mg, 72%). MS (ES+) m/z: 330.0 [(M+H) ⁺ ].

intermediate 7-9 : 2-bromo-8- (2,3,4-trifluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) Oxy)butan-1-ol (500 mg, 1.37 mmol, eq: 1, described above), 2,3,4-trifluorophenol (244 mg, 1.65 mmol, eq: 1.2) and triphenylphosphine (450) mg, 1.72 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-1-(methoxymethyl)-5-(4-((tetrahydro-2H- Obtained pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)butyl)-1H-1,2,4-triazole as a pale yellow oil (575 mg, 84%). did. MS (ES+) m/z: 412.0 (-THP) [(M+H) ⁺ ].

Step 2: 3-Bromo-1-(methoxymethyl)-5-(4-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy) cy)butyl)-1H-1,2,4-triazole (570 mg, 1.15 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.54 g, 3.79 ml, 46.1 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2,3) ,4-Trifluorophenoxy)butan-1-ol was obtained as a colorless viscous oil (400 mg, 94%). MS (ES+) m/z: 366.0 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2,3,4-trifluorophenoxy)butan-1-ol (395 mg , 1.08 mmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.7 ml, 1.35 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to RT and extracted with EtOAc (70 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back extracted with EtOAc (2x 40 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 2-bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetra Hydro-[1,2,4]triazolo[1,5-a]pyridine was obtained as a colorless oil (285 mg, 75%). MS (ES+) m/z: 347.9 [(M+H) ⁺ ].

intermediate 7-10 : 2-bromo-8- (2,4-difluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) oxy)butan-1-ol (495 mg, 1.36 mmol, eq: 1, described above), 2,4-difluorophenol (212 mg, 1.63 mmol, eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (344 mg, 330 μl, 1.7 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(2,4-difluorophenoxy)-4-( (Tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole was obtained as a colorless oil (549 mg, 84%). MS (ES+) m/z: 392.0 (-THP) [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(2,4-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxy Methyl)-1H-1,2,4-triazole (545 mg, 1.14 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and under argon, 37% HCl in water (4.51 g, 3.76 ml, 45.8 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2,4) -difluorophenoxy)butan-1-ol was obtained as a colorless solid (360 mg, 90%). MS (ES+) m/z: 348.0 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2,4-difluorophenoxy)butan-1-ol (355 mg, 1.02 mmol, Eq: 1) was combined with excess dry THF (10.5 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.55 ml, 1.27 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-8-(2,4-difluorophenoxy)-5,6,7,8-tetrahydro- [1,2,4]triazolo[1,5-a]pyridine was obtained as a colorless oil (285 mg, 75%). MS (ES+) m/z: 330.0 [(M+H) ⁺ ].

intermediate 7-11 : 2-bromo-8- (3-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) Oxy)butan-1-ol (500 mg, 1.37 mmol, eq: 1, eq.), 3-chlorophenol (212 mg, 1.65 mmol, eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, eq.) : 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3-chlorophenoxy)-4-((tetrahydro- Obtained 2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (560 mg, 85%). MS (ES+) m/z: 474.0 [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(3-chlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H -1,2,4-triazole (555 mg, 1.17 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and under argon, 37% HCl in water (4.61 g, 3.84 ml, 46.8 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3-chloro Phenoxy)butan-1-ol was obtained as a colorless viscous oil (375 mg, 92%). MS (ES+) m/z: 347.9 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3-chlorophenoxy)butan-1-ol (370 mg, 1.07 mmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.67 ml, 1.33 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-8-(3-chlorophenoxy)-5,6,7,8-tetrahydro-[1,2 ,4]triazolo[1,5-a]pyridine was obtained as a colorless oil (263 mg, 75%). MS (ES+) m/z: 329.9 [(M+H) ⁺ ].

intermediate 7-12 : 2-Bromo-8- (2-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) oxy)butan-1-ol (492 mg, 1.35 mmol, eq: 1, eq.), 2-chlorophenol (208 mg, 1.62 mmol, eq: 1.2) and triphenylphosphine (443 mg, 1.69 mmol, eq.) : 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(2-chlorophenoxy)-4-((tetrahydro- Obtained 2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (560 mg, 85%). MS (ES+) m/z: 392.0 (-THP) [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(2-chlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H -1,2,4-triazole (560 mg, 1.18 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and under argon, 37% HCl in water (4.65 g, 3.87 ml, 47.2 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. Cooled to RT, poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100), and 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2- Chlorophenoxy)butan-1-ol was obtained as a white solid (362 mg, 88%). MS (ES+) m/z: 347.9 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2-chlorophenoxy)butan-1-ol (360 mg, 1.04 mmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.6 ml, 1.3 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100), and 2-bromo-8-(2-chlorophenoxy)-5,6,7,8-tetrahydro-[1, 2,4]triazolo[1,5-a]pyridine was obtained as a white solid (260 mg, 76%). MS (ES+) m/z: 329.9 [(M+H) ⁺ ].

intermediate 7-13 : 2-Bromo-8- (4-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) Oxy)butan-1-ol (500 mg, 1.37 mmol, eq: 1, described above), 4-chlorophenol (212 mg, 1.65 mmol, eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, eq.) : 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(4-chlorophenoxy)-4-((tetrahydro- Obtained 2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (489 mg, 75%). MS (ES+) m/z: 474.9 [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(4-chlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H -1,2,4-triazole (485 mg, 1.02 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.03 g, 3.36 ml, 40.9 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(4-chloro Phenoxy)butan-1-ol was obtained as a colorless viscous oil (320 mg, 90%). MS (ES+) m/z: 347.9 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(4-chlorophenoxy)butan-1-ol (310 mg, 894 μmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.24 ml, 1.12 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to RT and extracted with EtOAc (70 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100), and 2-bromo-8-(4-chlorophenoxy)-5,6,7,8-tetrahydro-[1, 2,4]triazolo[1,5-a]pyridine was obtained as a white solid (182 mg, 61%). MS (ES+) m/z: 329.9 [(M+H) ⁺ ].

intermediate 7-14 : 2-Bromo-8- (3,5-dichlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) oxy)butan-1-ol (509 mg, 1.4 mmol, eq: 1, described above), 3,5-dichlorophenol (273 mg, 1.68 mmol, eq: 1.2) and triphenylphosphine (458 mg, 1.75) mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (353 mg, 340 μl, 1.75 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3,5-dichlorophenoxy)-4-(( Tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole was obtained as a colorless oil (670 mg, 94%). GCMS m/z: 423.9 (-THP) [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(3,5-dichlorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl )-1H-1,2,4-triazole (665 mg, 1.31 mmol, Eq: 1) was combined with MeOH (10 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (5.15 g, 4.29 ml, 52.2 mmol, Eq: 40) was added (exothermic). The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (40 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2x 80 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3,5) -Dichlorophenoxy)butan-1-ol was obtained as a white foam (435 mg, 87%). MS (ES+) m/z: 381.9 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3,5-dichlorophenoxy)butan-1-ol (430 mg, 1.13 mmol , equivalents: 1) was combined with excess dry THF (12 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.82 ml, 1.41 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to RT and extracted with EtOAc (100 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 50 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100), and 2-bromo-8-(3,5-dichlorophenoxy)-5,6,7,8-tetrahydro- [1,2,4]triazolo[1,5-a]pyridine was obtained as a white solid (285 mg, 69%). MS (ES+) m/z: 363.9 [(M+H) ⁺ ].

intermediate 7-15 : 2-bromo-8- (2,3-difluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) oxy)butan-1-ol (498 mg, 1.37 mmol, eq: 1, described above), 2,3-difluorophenol (213 mg, 1.64 mmol, eq: 1.2) and triphenylphosphine (448 mg, 1.71 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (346 mg, 332 μl, 1.71 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(2,3-difluorophenoxy)-4-( Obtained (tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a colorless oil (560 mg, 86%). GCMS m/z: 392.0 (-THP) [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(2,3-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxy) Methyl)-1H-1,2,4-triazole (555 mg, 1.17 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.59 g, 3.83 ml, 46.6 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (90 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(2,3) -difluorophenoxy)butan-1-ol was obtained as a colorless viscous oil (375 mg, 92%). MS (ES+) m/z: 348.0 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(2,3-difluorophenoxy)butan-1-ol (372 mg, 1.07 mmol, Eq: 1) was combined with excess dry THF (11 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.67 ml, 1.34 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100), and 2-bromo-8-(2,3-difluorophenoxy)-5,6,7,8-tetrahydro -[1,2,4]triazolo[1,5-a]pyridine Obtained as a white solid (255 mg, 72%). MS (ES+) m/z: 330.0 [(M+H) ⁺ ].

intermediate 7-16 : 2-bromo-8- (3,4-difluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-4-((tetrahydro-2H-pyran-2-yl) oxy)butan-1-ol (500 mg, 1.37 mmol, eq: 1, described above), 3,4-difluorophenol (214 mg, 1.65 mmol, eq: 1.2) and triphenylphosphine (450 mg, 1.72 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (347 mg, 334 μl, 1.72 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3,4-difluorophenoxy)-4-( (Tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxymethyl)-1H-1,2,4-triazole was obtained as a colorless oil (550 mg, 84%). MS (ES+) m/z: 392.0 (-THP) [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(3,4-difluorophenoxy)-4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1-(methoxy) Methyl)-1H-1,2,4-triazole (550 mg, 1.15 mmol, Eq: 1) was combined with MeOH (9 ml) to give a colorless solution. Under stirring and under argon, 37% HCl in water (4.55 g, 3.79 ml, 46.2 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (35 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 4-(3-bromo-1H-1,2,4-triazol-5-yl)-4-(3,4 Obtained -difluorophenoxy)butan-1-ol as a colorless viscous oil (385 mg, 95%). MS (ES+) m/z: 348.0 [(M+H) ⁺ ].

Step 3: 4-(3-Bromo-1H-1,2,4-triazol-5-yl)-4-(3,4-difluorophenoxy)butan-1-ol (380 mg, 1.09) mmol, Eq: 1) was combined with excess dry THF (12 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.73 ml, 1.36 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (80 ml) and saturated sodium bicarbonate solution (15 ml). The aqueous layer was back extracted with EtOAc (2x 60 ml). The organic layers were washed with brine (15 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 0:100) to 2-bromo-8-(3,4-difluorophenoxy)-5,6,7,8-tetrahydro- [1,2,4]triazolo[1,5-a]pyridine was obtained as a colorless oil (292 mg, 81%). MS (ES+) m/z: 330.0 [(M+H) ⁺ ].

1.2.3) intermediates of type 7, with m=3

intermediate 7-17 : 2-Bromo-9- (4-fluorophenoxy) -6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [1,5-a] azepine

Step 1: 3,5-Dibromo-1-(methoxymethyl)-1H-1,2,4-triazole (10.2 g, 37.7 mmol, Eq: 1, described above) is combined with THF (90 ml) to give a colorless solution. The mixture was then cooled to -75 °C in a dry ice/acetone bath. 1.6 M of n-butyllithium in hexanes (24.9 ml, 39.9 mmol, Eq: 1.06) was added dropwise over a period of 20 min. The yellow solution was stirred at -75 °C for 45 min. Then a solution of 5-((tetrahydro-2H-pyran-2-yl)oxy)pentanal (8.41 g, 45.2 mmol, Eq: 1.2) in THF (90 ml) was added dropwise over a period of 30 min. The mixture was then stirred at -75 °C for 45 min. The dry ice/acetone bath was removed and the reaction mixture was warmed to about 15 °C over 1 h. The reaction mixture was quenched with 190 ml saturated NH ₄ Cl-solution followed by 190 ml water and 250 ml EtOAc. The mixture was stirred for 5 minutes. The layers were separated. The aqueous layer was back extracted with EtOAc (2x 250 ml). The organic layers were washed with brine (200 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 80:20 to 20:80) to 1-(3-bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl )-5-((tetrahydro-2H-pyran-2-yl)oxy)pentan-1-ol was obtained as a pale yellow oil (11.4 g 80%). MS (ES+) m/z: 378.1/380.1 [(M+H) ⁺ ].

Step 2: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5-((tetrahydro-2H-pyran-2-yl) Oxy)pentan-1-ol (500 mg, 1.32 mmol, Eq: 1), 4-fluorophenol (178 mg, 1.59 mmol, Eq: 1.2) and triphenylphosphine (433 mg, 1.65 mmol, Eq: 1.25) ) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (334 mg, 321 μl, 1.65 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(4-fluorophenoxy)-5-((tetrahydro Obtained -2H-pyran-2-yl)oxy)pentyl)-1-(methoxymethyl)-1H-1,2,4-triazole as a pale yellow oil (485 mg, 77%). MS (ES+) m/z: 474.1 [(M+H) ⁺ ].

Step 3: 3-Bromo-5-(1-(4-fluorophenoxy)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-1-(methoxymethyl)- 1H-1,2,4-triazole (480 mg, 1.02 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colorless solution. Under stirring and argon, 37% HCl in water (4.01 g, 3.34 ml, 40.6 mmol, Eq: 40) was added. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction mixture was then cooled to RT and poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 90:10 to 0:100) to 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(4-fluoro Lophenoxy)pentan-1-ol (325 mg, 944 μmol, Eq: 1) was obtained as a colorless viscous oil (330 mg, 94%). MS (ES+) m/z: 346.0 [(M+H) ⁺ ].

Step 4: 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(4-fluorophenoxy)pentan-1-ol (325 mg, 944 μmol, equivalents : 1) was combined with excess dry THF (10 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.36 ml, 1.18 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (60 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back extracted with EtOAc (2x 40 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 2-bromo-9-(4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[ 1,2,4]triazolo[1,5-a]azepine was obtained as a colorless viscous oil (308 mg, 58%). MS (ES+) m/z: 326.0 [(M+H) ⁺ ].

intermediate 7-18 : 2-Bromo-9- (2,3,4-trifluorophenoxy) -6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [1,5- a]azepine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5-((tetrahydro-2H-pyran-2-yl) Oxy)pentan-1-ol (500 mg, 1.32 mmol, Eq: 1, described above), 2,3,4-trifluorophenol (235 mg, 1.59 mmol, Eq: 1.2) and triphenylphosphine (433) mg, 1.65 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (334 mg, 321 μl, 1.65 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-1-(methoxymethyl)-5-(5-((tetrahydro-2H- Obtained pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy)pentyl)-1H-1,2,4-triazole as a pale yellow oil (555 mg, 82%). did. MS (ES+) m/z: 508.1 [(M+H) ⁺ ].

Step 2: 3-Bromo-1-(methoxymethyl)-5-(5-((tetrahydro-2H-pyran-2-yl)oxy)-1-(2,3,4-trifluorophenoxy) cy)pentyl)-1H-1,2,4-triazole (550 mg, 1.08 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colorless solution. Under stirring and under argon, 37% HCl in water (4.26 g, 3.55 ml, 43.3 mmol, Eq: 40) was added (exothermic). The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. The reaction was then cooled to RT and poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 80:20 to 0:100) to 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(2,3) Obtained ,4-trifluorophenoxy)pentan-1-ol as a colorless oil (390 mg, 94%). MS (ES+) m/z: 380.0 [(M+H) ⁺ ].

Step 3: 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(2,3,4-trifluorophenoxy)pentan-1-ol (385 mg , 1.01 mmol, Eq: 1) was combined with excess dry THF (10 ml) to give a colorless solution. Under stirring and under argon, a solution of cyanomethylenetrimethylphosphorane (2.53 ml, 1.27 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (60 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back extracted with EtOAc (2x 40 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50), and 2-bromo-9-(2,3,4-fluorophenoxy)-6,7,8,9-tetra Hydro-5H-[1,2,4]triazolo[1,5-a]azepine was obtained as a white solid (225 mg, 61%). MS (ES+) m/z: 362.0 [(M+H) ⁺ ].

intermediate 7-19 : 2-Bromo-9- (3-chloro-5-fluorophenoxy) -6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [1,5-a ]azepine

Step 1: 1-(3-Bromo-1-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5-((tetrahydro-2H-pyran-2-yl) oxy)pentan-1-ol (500 mg, 1.32 mmol, eq: 1, described above), 3-chloro-5-fluorophenol (232 mg, 1.59 mmol, eq: 1.2) and triphenylphosphine (433 mg , 1.65 mmol, Eq: 1.25) was combined with THF (25 ml) to give a colorless solution. The reaction mixture was stirred in an ice bath and cooled under argon. DIAD (334 mg, 321 μl, 1.65 mmol, Eq: 1.25) was added dropwise over a period of 5 min at up to +3 °C. The ice bath was removed and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo and purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 3-bromo-5-(1-(3-chloro-5-fluorophenoxy)-5- ((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-1-(methoxymethyl)-1H-1,2,4-triazole was obtained as a colorless oil (565 mg, 84%). MS (ES+) m/z: 506.0 [(M+H) ⁺ ].

Step 2: 3-Bromo-5-(1-(3-chloro-5-fluorophenoxy)-5-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-1-(methyl Toxymethyl)-1H-1,2,4-triazole (560 mg, 1.1 mmol, Eq: 1) was combined with MeOH (8 ml) to give a colorless solution. 37% HCl in water (4.36 g, 3.63 ml, 44.2 mmol, Eq: 40) was added under stirring and argon. The reaction mixture was stirred without heating for 30 minutes, then at reflux for 1 h. Cooled to RT, poured into ice water (30 ml), neutralized with solid sodium bicarbonate and extracted with EtOAc (100 ml). The aqueous layer was back extracted with EtOAc (2x 70 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 80:20 to 0:100) to 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(3-chloro) Obtained -5-fluorophenoxy)pentan-1-ol as a colorless viscous oil (350 mg, 83%). MS (ES+) m/z: 379.9 [(M+H) ⁺ ].

Step 3: 5-(3-bromo-1H-1,2,4-triazol-5-yl)-5-(3-chloro-5-fluorophenoxy)pentan-1-ol (380 mg, 1 mmol, Eq: 1) was combined with excess dry THF (10 ml) to give a colorless solution. Under stirring and argon, a solution of cyanomethylenetrimethylphosphorane (2.51 ml, 1.25 mmol, Eq: 1.25) in THF (0.5M) was added dropwise over a period of 5 min. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was then cooled to RT and extracted with EtOAc (60 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was back extracted with EtOAc (2x 40 ml). The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by ISCO chromatography (Hept: EtOAc 95:5 to 50:50) to 2-bromo-9-(3-chloro-5-fluorophenoxy)-6,7,8,9-tetrahydro -5H-[1,2,4]triazolo[1,5-a]azepine was obtained as a colorless oil (218 mg, 60%). MS (ES+) m/z: 361.9 [(M+H) ⁺ ].

1.2.4) intermediates of type 8

intermediate 8-1 : (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: tert-Butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (500 mg, 2.21 mmol) in EtOH (10 mL) in a sealed tube ) and 4-chloro-6-methylpyrimidine (869 mg, 6.63 mmol) was added followed by triethylamine (894 mg, 1.23 mL, 8.84 mmol). The reaction mixture was stirred at 130 °C overnight. The crude reaction mixture was concentrated in vacuo. The residue was diluted with 20 mL of CH ₂ Cl ₂ and 20 mL of water. The organic phase _{was extracted with CH 2} Cl ₂ (3×20 mL), _{dried over MgSO 4} and concentrated in vacuo. The crude material was purified by flash chromatography (0% to 100% EtOAc in heptane), tert-butyl N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3 -azabicyclo[3.2.1]octan-8-yl]carbamate was obtained as a yellow solid (496 mg, 71 % yield). MS (ES+) m/z : 319.2 [(M+H) ⁺ ].

Step 2: tert-Butyl N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1] in _{CH 2} Cl _{2 (8 mL)} To a pale yellow solution of octan-8-yl]carbamate (260 mg, 817 μmol) was added TFA (931 mg, 629 μl, 8.17 mmol). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The crude material was purified by ion-exchange column (Si-SCX-2, 10 g, washed with MeOH _{and liberated with MeOH (NH 3} 2M)), (1R,5S,8S)-3-(6-methylpyri) Midin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 (195 mg, 804 μmol, 98.5 % yield) was obtained, which was used in the next step without further purification. MS (ES+) m/z : 219.2 [(M+H) ⁺ ].

intermediate 8-2 : (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

Step 1: Similar to the preparation of intermediate 8-1 (step 1), tert-butyl N-[(1R,5S,8S)-3-azabicyclo[(1R,5S,8S)-3-azabicyclo[] using EtOH as solvent at 90 °C in a sealed tube. 3.2.1] Octan-8-yl] carbamate (2.00 g, 8.84 mmol) and 3,5-dichloropyridazine (2.0 g, 13.4 mmol) of Et ₃ N (3.63 g, 5.0 mL, 35.9 mmol) In the presence of tert-butyl N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate ( 1.71 g, 54%) was obtained as a white solid. MS (ES+) m/z : 339.2 [(M+H) ⁺ ].

Step 2: tert-Butyl N-[(1R,5S,8S)-3-(6-chloropyridazin-4-yl)-3-azabicyclo[3.2.1] in MeOH (22 mL) in a sealed tube To a solution of octan-8-yl]carbamate (963 mg, 2.70 mmol) was added a methanol solution of NaOMe (25%, 1.9 mL, 8.3 mmol). The reaction mixture was heated at 85 °C overnight. The reaction mixture was adsorbed on Isolute HM-N and column chromatography, followed by tert-butyl N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1] octan-8-yl]carbamate (362 mg, 38%) was provided as a white solid. MS (ES+) m/z : 335.2 [(M+H) ⁺ ].

Step 3: Similar to the preparation of intermediate 8-1 (step 2), tert-butyl N-[(1R,5S,8S)-3-(6-methoxypyridazin-4-yl) in _{CH 2} Cl ₂ -3-azabicyclo[3.2.1]octan-8-yl]carbamate (0.93 g, 2.72 mmol) in the presence of TFA (1.12 g, 0.76 mL, 9.86 mmol) (1R,5S,8S)- 3-(6-Methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 (225 mg, 96%) was obtained as a white solid, which was further purified used directly in the next step. MS (ES+) m/z : 235.2 [(M+H) ⁺ ].

intermediate 8-3 : (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine

In a similar manner to intermediates 8-1 and 8-2 , tert-butyl N-[(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-yl]carbamate and 5-chloro Starting from -3-methyl-pyridazine the title compound 8-3 was prepared as a white solid. MS (ES+) m/z : 219.3 [(M+H) ⁺ ].

1.3) General Procedure 1: Buchwald Coupling Reaction

In a sealed tube, to a solution of intermediate 7 (0.25 mmol) in 2-Me-THF (7 ml) was added 1.0 equivalent of intermediate 8 . The reaction mixture was degassed and NaOtBu (1.5 equiv) was added at RT and stirring continued for 10 min followed by addition of tBu-Xphos (0.06 equiv) and Pd ₂ (dba) ₃ (0.03 equiv). The reaction mixture was heated at 70-80 °C until reaction completion (usually 1-3 hours) and concentrated in vacuo. Purification by flash column chromatography or reverse-phase preparative HPLC to the desired formula The product of (I) was obtained.

Examples 1 to 64 below are single enantiomers, but their absolute structures have not been determined. Enantiomers are mentioned in the examples in the order in which they eluted from the column.

Examples 1 and 2

(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

and

(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-1 and Between (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2, Buchwald using General Procedure 1 After type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 1): 27 mg, MS (ES+) m/z : 470.2 [(M+H) ⁺ ] and (Example 2): 28 mg, MS (ES+) m/z : 470.2 [(M+H) ⁺ ].

Examples 3 and 4

(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1] Octan-8-yl) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

and

(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1] Octan-8-yl) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

2-Bromo-7- (3-chloro-5-fluorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole 7-2 Buchwald using General Procedure 1 between (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 After type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 3): 18 mg, MS (ES+) m/z : 486.1 [(M+H) ⁺ ] and (Example 4): 20 mg, MS (ES+) m/z : 486.1 [(M+H) ⁺ ].

Examples 5 and 6

(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

and

(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

2-Bromo-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7- Between 3 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2, using General Procedure 1 After Buchwald-type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 5): 27 mg, MS (ES+) m/z : 488.2 [(M+H) ⁺ ] and (Example 6): 20 mg, MS (ES+) m/z : 488.2 [(M+H) ⁺ ].

Examples 7 and 8

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1] Octan-8-yl) -5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1] Octan-8-yl) -5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8- (3-chloro-5-fluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7 General procedure 1 between -7 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 After the Buchwald type coupling used, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 7): 34 mg, MS (ES+) m/z : 500.1 [(M+H) ) ⁺ ] and (Example 8): 31 mg, MS (ES+) m/z : 500.1 [(M+H) ⁺ ].

Examples 9 and 10

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7- Between 8 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 , using General Procedure 1 After Buchwald-type coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 9): 37 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ] and (Example 10): 36 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ].

Examples 11 and 12

(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine General procedure 1 between 7-9 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 After Buchwald-type coupling using , separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 11): 42 mg, MS (ES+) m/z : 502.2 [(M+) H) ⁺ ] and (Example 12): 41 mg, MS (ES+) m/z : 502.2 [(M+H) ⁺ ].

Examples 13 and 14

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8- (3-chloro-5-fluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7 Between -7 and (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-3 , using General Procedure 1 After Buchwald-type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 13): 32 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ] and (Example 14): 33 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ].

Examples 15 and 16

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7- Buch using General Procedure 1 between 8 and (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-3 After Baltic coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 15): 29 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ] and (Example 16): 25 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ].

Examples 17 and 18

(R)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine General procedure 1 between 7-9 and (1R,5S,8S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-3 After the Buchwald type coupling used, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 17): 26 mg, MS (ES+) m/z : 486.2 [(M+H) ) ⁺ ] and (Example 18): 26 mg, MS (ES+) m/z : 486.2 [(M+H) ⁺ ].

Examples 19 and 20

(R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(2,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7- Between 10 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 , using General Procedure 1 After Buchwald-type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 19): 28 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ] and (Example 20): 28 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ].

Examples 21 and 22

(R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(2,3-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7- Between 15 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 , using General Procedure 1 After Buchwald-type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 21): 27 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ] and (Example 22): 26 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ].

Examples 23 and 24

(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-bromo-8- (3-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7-11 and (1R Buchwald-type couple using General Procedure 1 between ,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 After ringing, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 23): 22 mg, MS (ES+) m/z : 482.2 [(M+H) ⁺ ] and ( Example 24): 22 mg, MS (ES+) m/z : 482.2 [(M+H) ⁺ ].

Examples 25 and 26

(R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8- (2-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7-12 and (1R Buchwald-type couple using General Procedure 1 between ,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2 After ringing, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 25): 26 mg, MS (ES+) m/z : 482.2 [(M+H) ⁺ ] and ( Example 26): 26 mg, MS (ES+) m/z : 482.2 [(M+H) ⁺ ].

Examples 27 and 28

(R)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

and

(S)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

2-Bromo-7- (4-chlorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole 7-4 and (1R,5S After Buchwald-type coupling using General Procedure 1 between ,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1, Separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 27): 36 mg, MS (ES+) m/z : 452.1 [(M+H) ⁺ ] and (Example 28) ): 36 mg, MS (ES+) m/z : 452.1 [(M+H) ⁺ ].

Examples 29 and 30

(R)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

and

(S)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

2-Bromo-7- (3-chlorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole 7-5 and (1R,5S After Buchwald-type coupling using General Procedure 1 between ,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1, Separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 29): 26 mg, MS (ES+) m/z : 452.1 [(M+H) ⁺ ] and (Example 30) ): 25 mg, MS (ES+) m/z : 452.1 [(M+H) ⁺ ].

Examples 31 and 32

(R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8- (2-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7-12 and (1R Buchwald-type coupling using General Procedure 1 between ,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 Subsequent separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 31): 20 mg, MS (ES+) m/z : 466.2 [(M+H) ⁺ ] and (run Example 32): 20 mg, MS (ES+) m/z : 466.2 [(M+H) ⁺ ].

Examples 33 and 34

(R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(2,3-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7- Buch using General Procedure 1 between 15 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Baltic coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 33): 36 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ] and (Example 34): 31 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ].

Examples 35 and 36

(R)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

and

(S)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

2-bromo-7- (3,5-dichlorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole 7-6 and ( Buchwald-type couple using General Procedure 1 between 1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After ringing, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 35): 27 mg, MS (ES+) m/z : 486.1 [(M+H) ⁺ ] and ( Example 36): 27 mg, MS (ES+) m/z : 486.1 [(M+H) ⁺ ].

Examples 37 and 38

(R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1] octane-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(2,4-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7- Buch using General Procedure 1 between 10 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Baltic coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 37): 34 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ] and (Example 38): 35 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ].

Examples 39 and 40

(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

and

(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-1 and Between (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 , the Buchwald form using General Procedure 1 After coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 39): 32 mg, MS (ES+) m/z : 454.2 [(M+H) ⁺ ] and (Example 40): 31 mg, MS (ES+) m/z : 454.2 [(M+H) ⁺ ].

Examples 41 and 42

(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-bromo-8- (3-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7-11 and (1R Buchwald-type coupling using General Procedure 1 between ,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 Subsequent separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 41): 30 mg, MS (ES+) m/z : 466.2 [(M+H) ⁺ ] and (run Example 42): 28 mg, MS (ES+) m/z : 466.2 [(M+H) ⁺ ].

Examples 43 and 44

(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(3,5-difluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 7- Buch using General Procedure 1 between 8 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Baltic coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 43): 36 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ] and (Example 44): 34 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ].

Examples 45 and 46

(R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-bromo-8- (4-chlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7-13 and (1R Buchwald-type coupling using General Procedure 1 between ,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 Subsequent separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 45): 27 mg, MS (ES+) m/z : 466.2 [(M+H) ⁺ ] and (run Example 46): 27 mg, MS (ES+) m/z : 466.2 [(M+H) ⁺ ].

Examples 47 and 48

(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

and

(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazol-2-amine

2-Bromo-7- (3-chloro-5-fluorophenoxy) -6,7-dihydro-5H-pyrrolo [1,2-b] [1,2,4] triazole 7-2 Buchwald using General Procedure 1 between (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 47): 28 mg, MS (ES+) m/z : 470.1 [(M+H) ⁺ ] and (Example 48): 27 mg, MS (ES+) m/z : 470.1 [(M+H) ⁺ ].

Examples 49 and 50

(R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8- (3,5-dichlorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7-14 Buchwald using General Procedure 1 between (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After type coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 49): 19 mg, MS (ES+) m/z : 500.1 [(M+H) ⁺ ] and (Example 50): 18 mg, MS (ES+) m/z : 500.1 [(M+H) ⁺ ].

Examples 51 and 52

(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2 ,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

and

(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2 ,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

2-Bromo-7-(2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7- Buch using General Procedure 1 between 3 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Baltic coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 51): 36 mg, MS (ES+) m/z : 472.2 [(M+H) ⁺ ] and (Example 52): 35 mg, MS (ES+) m/z : 472.2 [(M+H) ⁺ ].

Examples 53 and 54

(R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8- (3,4-difluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7- Buch using General Procedure 1 between 16 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Baltic coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 53): 35 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ] and (Example 54): 36 mg, MS (ES+) m/z : 468.2 [(M+H) ⁺ ].

Examples 55 and 56

(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8- (3-chloro-5-fluorophenoxy) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine 7 Between -7 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 , using General Procedure 1 After Buchwald-type coupling, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 55): 26 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ] and (Example 56): 26 mg, MS (ES+) m/z : 484.2 [(M+H) ⁺ ].

Examples 57 and 58

(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

and

(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

2-Bromo-8-(2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine General procedure 1 between 7 - 9 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After the Buchwald type coupling used, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 57): 27 mg, MS (ES+) m/z : 486.2 [(M+H) ) ⁺ ] and (Example 58): 29 mg, MS (ES+) m/z : 486.2 [(M+H) ⁺ ].

Examples 59 and 60

(R)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1] Octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

and

(S)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1] Octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

2-Bromo-9-(4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine 7- Buch using General Procedure 1 between 17 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Baltic coupling, separation of the enantiomers by preparative chiral HPLC gave the title product as a white solid (Example 59): 32 mg, MS (ES+) m/z : 464.2 [(M+H) ⁺ ] and (Example 60): 32 mg, MS (ES+) m/z : 464.2 [(M+H) ⁺ ].

Examples 61 and 62

(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2 ,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

and

(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2 ,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

2-Bromo-9-(2,3,4-fluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a] General procedure between azepine 7-18 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Buchwald type coupling with 1, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 61): 36 mg, MS (ES+) m/z : 500.2 [(M +H) ⁺ ] and (Example 62): 33 mg, MS (ES+) m/z : 500.2 [(M+H) ⁺ ].

Examples 63 and 64

(R)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

and

(S)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1] Octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine

2-Bromo-9- (3-chloro-5-fluorophenoxy) -6,7,8,9-tetrahydro-5H- [1,2,4] triazolo [1,5-a] General procedure between azepine 7-19 and (1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-1 After Buchwald type coupling with 1, the enantiomers were separated by preparative chiral HPLC to give the title product as a white solid (Example 63): 13 mg, MS (ES+) m/z : 498.2 [(M +H) ⁺ ] and (Example 64): 18 mg, MS (ES+) m/z : 498.2 [(M+H) ⁺ ].

2) Biological Example

2.1) Assay Procedure: Cell γ-Secretase Assay

Human glioma H4 cells overexpressing human APP695 with the Swedish double mutation (K595N/M596L) were plated at 30,000 cells/well/100 μL in 96 well plates of IMDM containing 10% FCS, 0.2 mg/L hygromycin B. and incubated at 37 °C, 5% CO _{2 .}

After 3-4 h of plating, dilute the compound in the medium and add 50 μL as a 1.5-fold concentrate to obtain the final concentration. Compounds were incubated for 24 h. Final doses typically range from 4 μM to 0.0013 μM in half-log steps, resulting in an 8-point dose response curve.

Appropriate controls and reference compounds using vehicle only were applied to this assay. The final concentration of Me ₂ SO was 0.4%.

After incubation at 37°C, 5% CO ₂ , secreted Aβ42 was quantified using the AlphaLisa® assay kit (human amyloid beta 1-42 kit, Perkin Elmer Inc.) as the supernatant. Transfer 20 μL of cell culture supernatant to the assay plate. Then 10 μL of a mixture of AlphaLisa®-conjugated capture antibody and biotinylated detection antibody was added and incubated at RT for 3 h with gentle shaking of the assay plate. After an additional 20 µL of Donor beads were added, the assay plates were incubated at RT for 30 min and continued shaking without exposure to direct sunlight. The assay plates were then read on a Paradigm AlphaLisa® reader using the built-in program for excitation at 680 nm and emission at 570 nm.

The measured signals were then used to calculate _{IC 50} values for inhibition of Aβ42 secretion by nonlinear regression fit analysis using XLfit 5.3 software (IDBS Ltd).

2.2) Results

The table below shows the data on inhibition of Aβ42 secretion of all compounds.

Claims (21)

A compound of formula (I): or a pharmaceutically acceptable salt thereof:

(I)
In the above formula,
R ¹ is halogen, lower alkyl, lower alkyl substituted with halogen, lower alkoxy or lower alkoxy substituted with halogen,
^{R 1} may be different when n is 2 or 3;
m is 1, 2 or 3;
n is 1, 2 or 3;
Ar is

and

a 6-membered heteroaryl group selected from;
R ² is hydrogen, halogen, lower alkyl, lower alkyl substituted with halogen, or lower alkoxy;
R ³ is hydrogen or halogen. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia):

(Ia)
wherein R ¹ , m, n and Ar are as defined in claim 1. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (lb):

(Ib)
wherein R ¹ , m, n and Ar are as defined in claim 1. 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ^{1 is halogen.} The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ^{1 is fluorine or chlorine.} 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein m is 1 or 2. 7. The method according to any one of claims 1 to 6,
Ar is

and

a 6 membered heteroaryl group selected from;
R ² is lower alkyl or lower alkoxy;
R ³ is hydrogen,
A compound of formula (I) or a pharmaceutically acceptable salt thereof. 8. The method according to any one of claims 1 to 7,
Ar is

and

a 6 membered heteroaryl group selected from;
R ² is methyl or methoxy;
R ³ is hydrogen,
A compound of formula (I) or a pharmaceutically acceptable salt thereof. 4. The method according to any one of claims 1 to 3,
R ¹ is halogen;
m is 1 or 2;
n is 1, 2 or 3;
Ar is

and

a 6 membered heteroaryl group selected from;
R ² is lower alkyl or lower alkoxy;
R ³ is hydrogen,
A compound of formula (I) or a pharmaceutically acceptable salt thereof. 4. The method according to any one of claims 1 to 3,
R ¹ is fluorine or chlorine,
m is 1 or 2;
n is 1, 2 or 3;
Ar is

and

a 6 membered heteroaryl group selected from;
R ² is methyl or methoxy;
R ³ is hydrogen,
A compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from:
(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(2-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(2,3-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(2,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2 ,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-(2 ,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;
(S)-9-(4-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2 ,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-9-(2 ,3,4-trifluorophenoxy)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;
(R)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine; and
(S)-9-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine. 12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, selected from:
(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-7-( 2,3,4-trifluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo [3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-( 2,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1] octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(4-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octane -8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,5-dichlorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2. 1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-8-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(S)-7-(3-chloro-5-fluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[ 3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine;
(R)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(S)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-8-(2 ,3,4-trifluorophenoxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine;
(R)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine; and
(S)-8-(3,4-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2 .1]octan-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine. A method for preparing a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, comprising:
reacting a compound of formula (7) with an amine of formula (8) to form a compound of formula (I), and
If necessary, converting the compound into a pharmaceutically acceptable salt thereof.
A manufacturing method comprising:

7

8
wherein Ar, R ¹ , n and m are as defined in any one of claims 1 to 12. The compound according to any one of claims 1 to 12, prepared according to the method of claim 13, or a pharmaceutically acceptable salt thereof. 15. A compound according to any one of claims 1 to 12 and 14, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 15. The disease of any one of claims 1 to 12 and 14, of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type, multi-infarct dementia, boxer's dementia or Down's syndrome. A compound or a pharmaceutically acceptable salt thereof for use in therapeutic and/or prophylactic treatment. Claim 1 for the therapeutic and/or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type, multi-infarct dementia, boxer's dementia or Down's syndrome Use of a compound according to any one of claims 12 to 14 or a pharmaceutically acceptable salt thereof. The manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type, multi-infarct dementia, boxer's dementia or Down's syndrome Use of the compound according to any one of claims 1 to 12 and 14 or a pharmaceutically acceptable salt thereof for A method for the therapeutic and/or prophylactic treatment of Alzheimer's disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hereditary cerebral hemorrhage with amyloidosis-Dutch type, multi-infarct dementia, boxer's dementia or Down's syndrome, said method A method of treatment comprising administering an effective amount of a compound as defined in any one of claims 1 to 12 and 14 or a pharmaceutically acceptable salt thereof. the aforementioned invention.